Opioid Control of Identified Midbrain GABAergic Synapses

阿片类药物对中脑 GABA 能突触的控制

基本信息

批准号：
7948798
负责人：
GREGORY Olaf HJELMSTAD
金额：
$ 37.53万
依托单位：
ERNEST GALLO CLINIC AND RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7948798
关键词：
Acute Addictive Behavior Agonist Alcoholism Animals Bathing Behavior Binge Eating Cations Cell Nucleus Cells Chronic Clinical Data Development Disease Disinhibition Drug Addiction Electrophysiology (science)Elements Exhibits Exposure to Globus Pallidus Grant In Vitro Individual Inhibitory Synapse Investigation Knowledge Label Lead Light Limbic System Long-Term Potentiation Measurement Mediating Methods Midbrain structure Modeling Morphine Motivation Neurons Neurotransmitters Nucleus Accumbens Opioid Opioid Receptor Pharmacological Treatment Physiological Play Population Presynaptic Receptors Presynaptic Terminals Probability Property Psychological reinforcement Rattus Relative (related person)Rewards Rhodopsin Role Slice Source Structure Synapses Synaptic Receptors Synaptic plasticity Techniques Tracer Ventral Tegmental Area Viral Virus Diseases Whole-Cell Recordings base design dopaminergic neuron extracellular gamma-Aminobutyric Acid improved in vivo mu opioid receptors neural circuit novel novel strategies patch clamp postsynaptic receptor relating to nervous system research study synaptic function tool

项目摘要

DESCRIPTION (provided by applicant): Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) play an important role in the rewarding and reinforcing effects of opioids. Within the VTA, opioids acting at the mu opioid receptor inhibit the release of GABA, which leads to the disinhibition of DA neurons (Johnson and North, 1992a). However, GABA synapses onto VTA DA neurons arise not only from local GABAergic neurons, but also from extrinsic sources, at least some of which are likely to be sensitive to opioids. Two major external sources of inhibition onto VTA neurons arise from the nucleus accumbens (NAc) and the ventral pallidum (VP), both of which have been strongly implicated in opioid reward. These inputs have not been well defined, largely due to the technical challenge of isolating individual connections. Nevertheless, our understanding of the neural circuitry underlying opioid reward requires a thorough investigation of the synaptic properties of these VTA afferents. In this grant, we will make use of recently developed optogenetic tools to independently activate axon terminals arising from either the NAc or the VP in conjunction with whole cell patch-clamp electrophysiology from VTA neurons in midbrain slices. This will allow us to compare and contrast these two inputs and to determine how they are regulated by both acute and chronic exposure to opioids. In addition, by combining this powerful technique with retrograde labeling of VTA neurons from particular projection targets, we will be able to determine the detailed microcircuitry of these afferents within the VTA. The data provided by these studies will provide critical information for the development of circuit based models of limbic system function. PUBLIC HEALTH RELEVANCE: Opioid receptors are clinical targets for the treatment of drug addiction, alcoholism and compulsive eating. These studies will enhance our knowledge of how opioid receptors control the neural circuitry underlying motivation and reinforcement. Understanding precisely how opioid receptors alter addictive behaviors will lead to improved pharmacological treatments for these disorders.

描述（由申请人提供）：中脑腹侧对接区域（VTA）中的多巴胺（DA）神经元在阿片类药物的奖励和增强作用中起着重要作用。在VTA中，作用于MU阿片受体的阿片类药物抑制了GABA的释放，这导致了DA神经元的抑制作用（Johnson and North，1992a）。但是，GABA突触到VTA DA神经元上不仅来自局部GABA能神经元，而且还来自外部源，至少有些可能对阿片类药物敏感。对VTA神经元的抑制作用的两个主要外部来源来自伏隔核（NAC）和腹侧颗粒（VP），它们都与阿片类药物的奖励相关。这些输入尚未得到很好的定义，这在很大程度上是由于隔离单个连接的技术挑战。然而，我们对阿片类药物奖励基础的神经回路的理解需要彻底研究这些VTA传入的突触特性。在这笔赠款中，我们将利用最近开发的光遗传学工具来独立激活由NAC或VP引起的轴突终端，以及与中脑切片中VTA神经元的全细胞贴片钳电生理学结合使用。这将使我们能够比较和对比这两个输入，并确定如何通过急性和长期暴露于阿片类药物来调节它们。此外，通过将这种强大的技术与来自特定投影目标的VTA神经元的逆行标记相结合，我们将能够确定VTA中这些传入者的详细微电路。这些研究提供的数据将为开发基于电路的边缘系统功能的模型提供关键信息。公共卫生相关性：阿片类药物受体是治疗药物成瘾，酒精中毒和强迫性饮食的临床靶标。这些研究将增强我们对阿片类药物受体如何控制动机和增强神经回路的知识。精确地了解阿片类药物受体如何改变成瘾行为将导致改善这些疾病的药理治疗。